tbuckley/cabot-search huggingface dataset:
Abstract 2878: Identification of immunosuppressive and tumor-promoting neutrophils in human bone marrow and a novel mouse model that supports human neutrophil engraftment
Authors: Wei Liu, Keying Che, Chun Lu, Jia Wei, Yan Li
Journal: Cancer Research (2023)

Abstract Immunosuppressive neutrophils are identified as a specialized heterogeneous population in cancer patients that accelerate tumor progression. However, the developmental stage and the source of this population remain elusive. To address this issue, we unified three reported neutrophil nomenclatures and demonstrated that immature neutrophils predominate tumor tissues of patients. On the quest to identify the origin of immature neutrophils, we unexpectedly discovered that immature neutrophils collected from the bone marrow of healthy people and mice reconstituted with human immune cells (HIS mice) are naturally immunosuppressive and tumor-promoting, whereas the mouse counterpart is not. Single-cell comparison of immature neutrophils isolated from human tumors, human bone marrow and HIS mouse bone marrow samples reveal FCN1 as a common marker for this heterogeneous population. To further investigate the link between peripheral and bone marrow immature neutrophils, we created a novel immunodeficient strain, to overcome the poor human neutrophil engraftment in the periphery. HIS mice based on this strain manifest similar kinetics of immature neutrophil expansion as cancer patients both in the bone marrow and periphery after tumor cell inoculation. Finally, we proved that eliminating bone marrow immature neutrophils delays tumor growth in HIS mice. In summary, human immunosuppressive neutrophils are predominantly immature neutrophils and targeting this population in bone marrow may represent a novel strategy for cancer immunotherapy. Citation Format: Wei Liu, Keying Che, Chun Lu, Jia Wei, Yan Li. Identification of immunosuppressive and tumor-promoting neutrophils in human bone marrow and a novel mouse model that supports human neutrophil engraftment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2878.
Abstract 2470: ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with <i>Pten</i> deficiency
Authors: Jae-Wook Jeong, Dinh Tran, Valery Rozen, Tae Hoon Kim, Jung-Yoon Yoo
Journal: Cancer Research (2023)

Abstract Endometrial cancer is the most common gynecologic malignancy. The most common histological type is endometrioid endometrial cancer (EEC). While the majority of patients present with early-stage and low-grade EEC and have an excellent prognosis, a subset has metastatic disease at presentation, or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EEC is a critical barrier. We have developed a genetically engineered mouse model for metastatic EEC that implicates coexistent Pten and Mig-6 mutations in EEC. Pten mutation in the uterus is not sufficient for distant metastasis, but mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers including ovarian carcinoma, colorectal cancer, and neuroblastoma. In the present study, ARG1 expression was evaluated with immunohistochemistry in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. Our immunostaining analysis revealed that the expression of ARG1 in early stage of EEC from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. High levels of ARG1 are associated with distant metastatic endometrial cancer. The results demonstrate that a high level of ARG1 is associated with poor prognosis in association with EEC of mouse. ARG1 has the potential to identify patients that require additional treatment at an early stage of endometrial cancer. Citation Format: Jae-Wook Jeong, Dinh Tran, Valery Rozen, Tae Hoon Kim, Jung-Yoon Yoo. ARG1 is potential prognostic biomarker for development of distant metastatic endometrial cancer in mice with Pten deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2470.
Abstract 5820: Chloroquine inhibited Rab11 mediated E-cadherin transport in collective colon cell migration in Dasatinib resistant cells
Authors: Xiang-Ling Hou, Hui Min Koo, Chia-Wen Lin, Chien-Chi Huang, Yu-Chi Tseng, Kai-Yu Tseng, Wei-Ting Chao
Journal: Cancer Research (2023)

Abstract In has been demonstrated epithelial mesenchymal transition (EMT) is related to E-cadherin expression level. Recently, studies have been demonstrated the collective cancer cell migration which expresses high E-cadherin is a powerful mechanism of metastasis. Therefore, the role of E-cadherin in cancer metastasis is still not clear. Endocytosis was shown to regulate E-cadherin turnover on the membrane and the function of lysosome is also associated with cell vesicle trafficking. The past studies indicated Src can regulate vesicle trafficking. In this study, HT29 colon cancer cells were treated with Src inhibitor, Dasatinib (DST), to investigate the role of lysosome in regulating E-cadherin dynamics through vesicle trafficking in collective cell migration. In the result, the recycling protein Rab11 and lysosome marker Lamp1 were found localized with E-cadherin in the cell-cell contacts, however, Dasatinib sensitive (DSTS) cells showed less colocalization of Rab11 with E-cadherin. When cells were treated with lysosome inhibitor chloroquine, Rab11 were accumulated in the cell-cell contacts and reduced collective cell migration in Dasatinib resistant (DSTR) cells. These results suggest lysosome inhibition can suppress Rab11 mediated vesicle trafficking of E-cadherin transport for collective cell migration, and chloroquine has therapeutic potential in colon cancer treatment. Citation Format: Xiang-Ling Hou, Hui Min Koo, Chia-Wen Lin, Chien-Chi Huang, Yu-Chi Tseng, Kai-Yu Tseng, Wei-Ting Chao. Chloroquine inhibited Rab11 mediated E-cadherin transport in collective colon cell migration in Dasatinib resistant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5820.
Abstract 6227: Tumor cell heterogeneity may cause treatment failure of GPA33-targeted therapy in colorectal cancer
Authors: Teresa Börding, Tobias Janik, Markus Morkel, Christine Sers, David Horst
Journal: Cancer Research (2023)

Abstract Purpose: Glycoprotein A33 (GPA33) is a membrane protein almost exclusively expressed in intestinal epithelia and in more than 95% of colorectal cancers (CRCs). This renders GPA33 a promising antigen for targeted therapy, but trials did not meet pre-specified response rates. We investigated intratumoral heterogeneity as a reason for low treatment efficacy, GPA33 regulation and the potential for pharmacological induction of GPA33 expression in vitro and in vivo to enhance treatment response. Methods: We assessed intratumoral heterogeneity of GPA33 in tissue specimens of 223 stage II CRCs using immunohistochemistry and immunofluorescence, and obtained scRNAseq transcriptomic analysis from 12 primary CRCs. We then manipulated WNT and PPARγ signaling pathways and transcription factor expression in colon cancer cells using specific inhibitors, siRNAs or inducible dominant negative TCF4 (dnTCF4), and analyzed the effects on GPA33 protein and RNA expression. Furthermore, we investigated the effects of WNT inhibition on GPA33 in vivo in NOD/SCID xenografts. Additionally, we developed anti-GPA33 CAR-T cells and measured their activation after co-cultivation with colon cancer cells using flow cytometry. Results: In the CRC cohort we found that GPA33 expressing cells had a differentiated phenotype and low WNT activity. GPA33-negative subpopulations were located at the infiltrative tumor edge and showed increased nuclear β-catenin. Downregulation of WNT pathway activity using inhibitors, siRNAs or inducible dominant negative TCF4 (dnTCF4), as well as activation of PPARγ signaling induced GPA33 expression in vitro. Forced expression of dnTCF4 also enhanced GPA33 expression in vivo in previously GPA33-negative tumor cell subpopulations in colon cancer xenografts. siRNA mediated knockdown of CDX1 and KLF4, two transcription factors that were previously implicated in GPA33 regulation, only moderately reduced GPA33 expression levels in vitro. Anti-GPA33 CAR-T cells activated in response to co-culture with GPA33-expressing CRC cells in vitro. Conclusion: Our analysis highlights a heterogenous expression of GPA33 in vivo as a limiting factor for anti-GPA33 therapy. WNT inhibition or PPARγ activation induced GPA33 expression in vitro and in vivo. Depletion of CDX1 and KLF4 had moderate effects on GPA33 only, indicating a complex regulation in colon cancer. We suggest that pharmacological induction of GPA33 expression may increase the efficacy of anti-GPA33 targeted therapy in patients with CRC. Citation Format: Teresa Börding, Tobias Janik, Markus Morkel, Christine Sers, David Horst. Tumor cell heterogeneity may cause treatment failure of GPA33-targeted therapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6227.
Abstract 143: A platform for deep evolutionary profiling of cancer resistance
Authors: Arvind Ravi, Sainikhil Sontha, Maisha Chowdhury, Jacob Smigiel, Matthew Rees, Brian Danysh, Jennifer Roth, Laxmi Parida, Eric Lander, Gad Getz
Journal: Cancer Research (2023)

Abstract Despite the introduction of a number of new therapeutic classes including targeted inhibitors, immunotherapy, and antibody-drug conjugates, the ability to achieve long-term disease control in the majority of patients with advanced cancer remains elusive due to the emergence of resistance. While our understanding of resistance mechanisms continues to expand through preclinical and clinical sequencing efforts, comprehensive approaches to map the distribution of potential resistance mechanisms in a given cell line and drug context require the development of novel approaches. Here, we describe the design of a platform for profiling cancer resistance at scale. Beginning with a single sensitive parental cancer cell line, the EGFR-mutant lung cancer line PC9, we optimize pre-existing diversity using a combination of single-cell subcloning and alkylator mutagenesis, and generate 50 independently evolved clones resistant to the EGFR inhibitor osimertinib. Profiling of this library via multiplexed whole genome sequencing (WGS) demonstrates convergent mutations in the MAPK pathway. Taking a similar approach, we profile the NTRK1-fusion-driven KM12 colon cancer cell line, yielding convergent, clinically observed, on-target resistance mutations to the NTRK inhibitor larotrectinib. Taken together, these results provide an initial proof-of-concept for the high-throughput generation of viable drug-resistant cancer clones. Future efforts to increase mutational diversity as well as assess additional drug and disease contexts will broaden the utility of this approach. Citation Format: Arvind Ravi, Sainikhil Sontha, Maisha Chowdhury, Jacob Smigiel, Matthew Rees, Brian Danysh, Jennifer Roth, Laxmi Parida, Eric Lander, Gad Getz. A platform for deep evolutionary profiling of cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 143.
Abstract 2884: Cancer-associated fibroblasts potentiate subcutaneous tumor growth in a novel bladder cancer mouse model with a genotype dependency
Authors: Henkel Lee Valentine, Uttam Satyal, Alexander Metz, Laura Bukavina, Philip H. Abbosh
Journal: Cancer Research (2023)

Abstract Introduction Interrogation of the relationship of genotype (mutation in relevant gene) and phenotype (sensitivity to therapy) in targeted therapy would be facilitated by the use of isogenic in vitro and in vivo models. The PI3K/AKT/mTOR pathway is widely activated but heretofore untargeted in bladder cancer. We sought to develop an immunocompetent CRISPR-edited bladder cancer mouse model that recapitulates common PI3K/AKT/mTOR mutations to study a genotype-phenotype relationship. Our in vitro CRISPR-edited organoids are immunogenic in vivo, as such, we explored utilizing Cancer-Associated Fibroblasts (CAFs) to mediate immunosuppression and promote a pro-tumorigenic environment. Methods and Results We isolated bladder urothelial cells from Rosa26 LSL-Cas9/GFP transgenic mice and grew them as organoids. Trp53 and Rb1 were co-edited to establish ‘base organoids’. As proof of concept, Pten was edited in base organoids in anticipation of developing a series of organoids with different mTOR pathway genotypes. We found that Pten-KO base organoids were 9x more sensitive to ipatasertib than Pten WT organoids. The edited urothelial cells were engrafted into mouse bladder to further test kinase inhibitor susceptibility as preclinical evidence to support human clinical trials. However, the cells successfully engrafted but disappeared after 3-4 weeks before tumors formed. Subcutaneous allografts were also rejected after 3-4 weeks and showed CD45+ immune infiltration during rejection. When cells were injected subcutaneously with CAFs, tumors persisted for 12 weeks, but only in organoids with both Trp53 loss and loss of murine chromosome 4qC4 (which is homologous to 9p21 loss in humans). 9p21 contains 3 genes which are co-deleted in ~40% of bladder cancers: MTAP, CDKN2A, and CDKN2B. Histopathological analysis of these masses confirmed their malignant nature and revealed an immune-excluded architecture. IHC staining of 9p21/Trp53 KO tumors for CD206 and CD11c revealed greater recruitment of M2 macrophages than M1 macrophages. Conclusions CAFs remodel the tumor-microenvironment in bladder cancer via the recruitment of pro-tumorigenic M2 macrophages. This may occur in a genotype-specific manner and 9p21 loss may be a requirement for some genotypes to be tumorigenic. Citation Format: Henkel Lee Valentine, Uttam Satyal, Alexander Metz, Laura Bukavina, Philip H. Abbosh. Cancer-associated fibroblasts potentiate subcutaneous tumor growth in a novel bladder cancer mouse model with a genotype dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2884.
Abstract 4209: Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System
Authors: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu
Journal: Cancer Research (2023)

Abstract Background: Cancers of unknown primary (CUP), a group of heterogenous metastatic cancers lacking a known primary site, have poor prognosis. This study compared survival by histologic type, patient characteristics, and treatment in the U.S. Military Health System (MHS), which provides universal care to its members. Methods: Patients diagnosed with CUP were identified from the U.S. Department of Defense’s Automated Central Tumor Registry. Median survival with 95% confidence intervals was calculated for demographic and treatment variables by histologic type. A multivariable accelerated failure time model estimated time ratios and 95% confidence intervals. Results: The study included 3,358 CUP patients. The most prevalent CUP in this study was well and moderately differentiated adenocarcinomas. Median survival varied by histologic type with squamous cell carcinoma having the longest at 25.1 months and poorly differentiated carcinomas having the shortest at 3.0 months. For each histologic type, survival was generally similar by sex and active-duty status. Younger patients tended to have longer survival than those aged 65 years or older. Women with well and moderately differentiated adenocarcinoma had longer survival than their male counterparts. Generally, there were no racial differences in survival except poorer survival for Blacks than Whites with other histologic types. Patents with chemotherapy and radiation treatment generally had improved survival whereas patients with squamous cell carcinoma who received chemotherapy had shorter survival than those without. Conclusion: Survival generally did not differ between racial groups, which may be related to equal healthcare access despite racial background. Further studies are warranted to better understand how survival in the MHS compares with that in the general U.S. population. Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of USUHS, HJF, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products or organizations does not imply endorsement by the US Government. Citation Format: Julie A. Bytnar, Jie Lin, Joel T. Moncur, Craig D. Shriver, Kangmin Zhu. Cancers of unknown primary: survival by histologic type, demographic features, and treatment in the US Military Health System. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4209.
Abstract 5793: Met confers radioresistance-associated aggressiveness through enhancing PLXDC2-mediated cancer stem cell plasticity
Authors: Fanghui Chen, Liwei Lang, Chloe Shay, Georgia Chen, Nabil Saba, Yong Teng
Journal: Cancer Research (2023)

Abstract The development of radioresistance in head and neck squamous cell carcinoma (HNSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in the past decades. One of the clinical challenges is that radioresistance often promotes tumor aggressiveness. However, the underlying mechanisms and molecular determinants are largely unknown. We report here that radioresistance-associated HNSCC aggressiveness is effectively exacerbated by c-Met but can be suppressed by its genetic knockdown and pharmacological inactivation. Through unbiased RNAseq data, we further uncovered that the resulting upregulation of c-Met signaling increases the expression of PLXDC2. a critical gene associated with the tumor microenvironment. Mechanistically, PLXDC2 is upregulated in radioresistant HNSCC cells through c-Met mediated activation of ERK1/2-ELK1 signaling cascade. Most importantly, PLXDC2 modulates cancer cell plasticity by inducing epithelial-mesenchymal transition (EMT) and the emergence of cancer stem cell (CSC) subpopulation. Additionally, depletion of PLXDC2 overcomes c-Met-mediated radioresistance by reversing the EMT progress and blunting the self-renewal capacity of CSCs. Therapeutically, a combination of the c-Met selective inhibitor SU11274 with radiation remarkably induces tumor shrinkage and constrains tumor metastasis to lymph nodes in vivo. Our study is novel in being the first to explore the role and mechanism of the c-Met-PLXDC2 axis in radioresistance-associated HNSCC aggressiveness and the first to our knowledge to evaluate how to take advantage of blocking this signaling to overcome radioresistance in preclinical mouse models of HNSCC. Citation Format: Fanghui Chen, Liwei Lang, Chloe Shay, Georgia Chen, Nabil Saba, Yong Teng. Met confers radioresistance-associated aggressiveness through enhancing PLXDC2-mediated cancer stem cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5793.
Abstract 4965: Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers
Authors: James D. Joseph, Katherine Schutt, Kira Fisher, Katelyn Queen, Olivia Budington, Weifeng Mao, Wei Liu, Zhengqing Zhu, Xiangping Zhang, Yisong Xiao, Kunmin Lai, Xiaohui Gu, Jason Stumpff, Fred Aswad
Journal: Cancer Research (2023)

Abstract Background: Chromosome instability (CIN), characterized by frequent and ongoing loss or gain of chromosome number, is commonly observed in tumor cells. Although long recognized as a vulnerability of cancer cells, potential CIN-selective therapeutic targets have only recently been discovered. Genetic studies from multiple groups have identified the mitotic kinesin, KIF18A, as selectively essential for the proliferation of CIN and aneuploid cells. By targeting KIF18A genetically and with novel small molecule inhibitors here we present data supporting KIF18A as therapeutic target in CIN tumors. Methods and Materials: To explore the therapeutic potential of KIF18A, we evaluated the effects of KIF18A genetic depletion and small molecule inhibition in both CIN-positive and CIN-negative cell lines. Biochemical, cell proliferation and phenotypic assays were used to characterize the potency and cellular activity of reference and novel KIF18A small molecule inhibitors. Anti-tumor activity of KIF18A inhibitors was assessed in CIN-positive cell line xenograft models. Results: In triple negative breast and colorectal CIN positive cancer cell lines siRNA mediated KIF18A knockdown and small molecule inhibition of the KIF18A ATPase activity both lead to a reduction in proliferation associated with an increase in mitotic index and multi-polar spindles. Consistent with KIF18A knockdown, KIF18A inhibition results in increased spindle length and chromosome alignment defects. Importantly, these effects are not observed with KIF18A knockdown or KIF18A inhibition in non-transformed, near diploid cells. In vivo, treatment of CIN-positive xenograft tumors with potent, novel KIF18A inhibitors results in robust anti-tumor activity with minimal impact on body weight. Conclusions: Collectively our data support KIF18A as a therapeutic target and provide rationale for the continued development of potent selective small molecule KIF18A inhibitors for the treatment of CIN positive cancers. Citation Format: James D. Joseph, Katherine Schutt, Kira Fisher, Katelyn Queen, Olivia Budington, Weifeng Mao, Wei Liu, Zhengqing Zhu, Xiangping Zhang, Yisong Xiao, Kunmin Lai, Xiaohui Gu, Jason Stumpff, Fred Aswad. Targeting the mitotic kinesin, KIF18A, in chromosomally unstable cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4965.